Sequential hydroarylation/Prins cyclization: an efficient strategy for the synthesis of angularly fused tetrahydro-2H-pyrano[3,4-c]quinolines

Abstract

Various aldehydes undergo a smooth cascade cyclization with N-(5-hydroxypent-2-yn-1-yl)-4-methyl-N-phenylbenzenesulfonamide in the presence of 10 mol% Ph₃PAuCl/AgSbF₆/In(OTf)₃ to furnish the corresponding tetrahydro-2H-pyrano[3,4-c]quinoline derivatives in good yields with high selectivity. This is the first report on the synthesis of tetrahydro-2H-pyrano[3,4-c]quinolines through a tandem hydroarylation/Prins cyclization process.

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Introduction

Nitrogen-containing heterocycles are common motifs in natural and synthetic molecules of pharmaceutical and agrochemical significance.¹ Among them, quinolin-2(1H)-one and its derivatives are ubiquitous subunits of numerous natural products, as well as being an extremely important class of heterocycles due to their wide range of applications in medicinal chemistry.^2–5 In particular, the pyranoquinoline skeleton is often found in various natural products (Fig. 1).⁶ These alkaloids and their derivatives possess a wide range of pharmacological activities such as anti-allergic, anti-inflammatory, anti-pyretic, psychotropic and anti-platelet properties.^7,8 Thus, the synthesis of pyranoquinoline derivatives is, currently, of great interest.

Fig. 1 Examples of bioactive pyranoquinolines.

Recently, there is a remarkable advancement in Prins cyclization for the stereoselective synthesis of oxygen containing heterocycles.⁹ In particular, its intramolecular variation provides a large number of fused/bridged heterocycles and spirocycles such as bicyclo[3.3.1]nonanes, bicyclo[3,2,1]octanes, and oxaspirobicycles.¹⁰ Therefore, it has become a powerful tool for the stereoselective construction of fused-, bridged- and spiro-skeletons. In spite of its potential application in natural products synthesis,¹¹ the scope of this tandem approach has not yet been explored to produce angularly fused tetrahydro-2H-pyrano[3,4-c]quinolines from readily accessible aldehydes and aryl tethered alkynols. Recently, metal catalyzed hydroarylation of alkynes has gained importance in the synthesis of biologically important heterocycles.¹² Among them, Au-catalyzed hydroarylation of alkynes has attained utmost popularity due to their high alkynophilicity and Lewis acidity to promote further C–C or C–X bond formation.^13,14

Results and discussions

Inspired by a recent advancement in multi-catalyst system,¹⁵ we herein disclose a novel cascade strategy for the one-pot synthesis of tetrahydro-2H-pyrano[3,4-c]quinoline derivatives from N-(5-hydroxypent-2-yn-1-yl)-4-methyl-N-phenylbenzene sulfonamide and aldehydes through a multi-catalytic cascade process. As a model reaction, we attempted the coupling of 4a with p-anisaldehyde (5a) using different catalysts. Accordingly, we performed a systematic screening of catalysts in the above reaction (Table 1). To our surprise, no desired product (6a) was obtained by using various Lewis acids such as InCl₃, Sc(OTf)₃, BF₃·OEt₂, TMSOTf and AgSbF₆ (entries a–e, Table 1). However, the use of 10 mol% In(OTf)₃ gave the expected product 6a in low to moderate yields (entries f and g, Table 1). These initial findings prompted us to find out an effective catalytic system for this reaction. Therefore, we further performed this reaction using the combination of In(OTf)₃ and AgSbF₆. But there was no significant improvement in yield (entry h, Table 1). Furthermore, the use of 10 mol% PPh₃AuCl also didn't give the desired product (entry i, Table 1). Though the combination of PPh₃AuCl/AgSbF₆ facilitates the initial hydroarylation, it fails to give the desired product (entry j, Table 1). After screening several catalysts, 10 mol% Ph₃PAuCl/AgSbF₆/In(OTf)₃ in DCE at 0 °C was found to be the best optimized conditions to achieve the product in excellent yield (entry k, Table 1).

Table 1 Optimization of reaction conditions

Entry	Lewis acid	Equiv.	Solvent	Temp. (°C)	Time (h)	Yield^a (%)
a Yield refers to pure products after column chromatography.
a	lnCl3	0.1	DCM	rt	12	—
b	Sc(OTf)3	0.1	DCM	rt	12	—
c	BF3·OEt2	1.0	DCM	rt	12	—
d	TMSOTf	1.0	DCM	rt	12	—
e	AgSbF6	0.1	DCM	rt	12	—
f	ln(OTf)3	0.1	DCM	rt	12	10
g	ln(OTf)3	0.1	DCE	70	2	60
h	ln(OTf)3/AgSbF6	0.1	DCE	rt	2	62
i	PPh3AuCl	0.1	DCM	rt	12	—
j	PPh3AuCl/AgSbF6	0.1	DCM	rt	12	—
k	PPh3AuCl/AgSbF6/ln(OTf)3	0.1	DCE	0	2	88

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In the above catalytic system, Au(I) activates the alkyne moiety to facilitate the hydroarylation and AgSbF₆ is expected to accelerate the reaction by generating active Au(I) cationic species. In(OTf)₃ acts as a Lewis acid and hence it activates the aldehyde effectively. Therefore, the cooperative effect of these catalysts facilitates this cascade process. As shown in Table 1, the combination of 10 mol% of each catalyst gave the product 6a in 88% after 2.0 h in dichloroethane at 0 °C (entry k, Table 1). No further increase in yield of 6a was observed by elevating the temperature to 25 °C. After successful standardization of reaction conditions, we extended this method to other aldehydes. Interestingly, different aldehydes including aromatic and aliphatic participated well in this cascade process. As shown in Table 2, the substituent present on the aromatic ring showed some effect on the conversion. Indeed, electron rich aldehydes such as p-methoxy-, p-methyl- and p-ethyl benzaldehydes gave the product relatively in higher yields (entries a, g, and l, Table 2) than electron deficient substrates (entries c, e, and f, Table 2). Among halogenated aromatic aldehydes, p- or o-bromobenzaldehyde afforded the product relatively in higher yield than fluoro- or chloro-substituted aromatic aldehyde (entries b, o and h Table 2). Among heterocyclic aldehydes, thiophene-2-carboxaldehyde gave the product relatively in good yield (entry i, Table 2). However, aliphatic aldehydes such as n-propanal and isobutyraldehyde furnished the products comparatively in lower yields (entries j, and k, Table 2) than aromatic and heterocyclic substrates. Furthermore, sterically hindered substrates, for example, 1-naphthaldehyde and 2-bromobenzaldehyde (entries m and n, Table 2) participated well in this reaction. The scope of the reaction was further illustrated with respect to ketones such as α-tetralone and N-methylisatin. However, these cyclic ketones failed to undergo this domino cyclization (entries p and q, Table 2). The reaction was performed with different N-protecting groups such as N-benzyl and N-mesyl and with unprotected NH. To our surprise, no desired product was formed when the reaction was conducted with substrates bearing N-benzyl and NH groups (entry t, Table 2). Low yield (20%) was achieved with N-mesyl group (entry r, Table 2). The reaction was quite successful only with N-Ts group (Table 2). This method is further extended to other substrates like N-(5-hydroxypent-2-yn-1-yl)-4-methyl-N-phenylbenzenesulfonamide and 5-(3,4,5-trimethoxyphenoxy)pent-3-yn-1-ol. The reaction between N-(5-hydroxypent-2-yn-1-yl)-4-methyl-N-phenylbenzenesulfonamide and p-fluorobenzaldehyde failed to give the desired product (entry s, Table 2). Similarly, the reaction of 5-(3,4,5-trimethoxyphenoxy)pent-3-yn-1-ol with pyridine-2-carboxaldehyde also didn't give the expected product under the present reaction conditions. The structure of 6j was confirmed by a single crystal X-ray diffraction (Fig. 2).¹⁶

Table 2 Synthesis of tetrahydro-2H-pyrano[3,4-c]quinolines^a

Entry	Aldehyde (5)	Product (6)	Yield^a (%)
a Yield refers to pure products after column chromatography.
a			88
b			75
c			71
d			80
e			69
f			77
g			80
h			76
i			78
j			68
k			67
l			80
m			82
n			78
o			68
p			—
q			—
r			20
s			—
t			—

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Fig. 2 ORTEP diagram of 6j.

The reaction was proposed to be proceeded through the formation of Au–π complex (A) by a coordination of cationic Au(I) species with alkyne moiety. A subsequent attack of the aryl group affords the cyclic vinylidene–Au complex (B). Concurrently, the pendent alcohol reacts with aldehyde activated likely by In(III) to afford the E-oxocarbenium ion (C), which is trapped intramolecularly by a gold vinylidene species to produce the tetrahydropyranoquinoline (6) with a regeneration of the gold catalyst (Scheme 1).

Scheme 1 A plausible reaction pathway.

On the other hand, In(OTf)₃ alone can activate the alkyne under heating conditions to facilitate the cyclization.¹⁷

Conclusion

In summary, a novel cascade strategy has been developed for the synthesis of tetrahydro-2H-pyrano[3,4-c]quinoline derivatives using a trifunctional catalytic system. This method facilitates the sequential formation of C–C, C–O, and C–C bonds with a wide substrate scope under relatively mild and neutral conditions, which makes it an attractive strategy. This approach demonstrates the synergism between gold, silver and indium complexes for domino cyclization.

Experimental section

General

All the solvents were dried according to standard literature procedures. Reactions were performed in oven-dried round bottom flask, the flasks were fitted with rubber septa and reactions were conducted under nitrogen atmosphere. Glass syringes were used to transfer solvent. Crude products were purified by column chromatography on silica gel of 60–120 or 100–200 mesh. Thin layer chromatography plates were visualized by exposure to ultraviolet light and/or by exposure to iodine vapors and/or by exposure to methanolic acidic solution of p-anisaldehyde followed by heating (<1 min) on a hot plate (∼250 °C). Organic solutions were concentrated on rotary evaporator at 35–40 °C. IR spectra were recorded on FT-IR spectrometer. ¹H NMR and ¹³C NMR (proton-decoupled) spectra were recorded in CDCl₃ solvent on 200, 300, 400 or 500 MHz NMR spectrometer. Chemical shifts (δ) were reported in parts per million (ppm) with respect to TMS as an internal standard. Coupling constants (J) are quoted in hertz (Hz). Mass spectra were recorded on mass spectrometer by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) technique.

Typical procedure. To a solution of N-(3,5-dimethoxyphenyl)-N-(5-hydroxypent-2-yn-1-yl)-4-methylbenzene sulfonamide (4a) (1 equiv., 0.05 g) and aldehyde (5) (1.5 equiv.) in anhydrous DCE (2 mL) was added PPh₃AuCl/AgSbF₆/In(OTf)₃ (all three catalysts 10 mol% each) at 0 °C. The resulting mixture was allowed to stir at 25 °C under nitrogen atmosphere for 2 h. After completion, the reaction mass was quenched with NaHCO₃ solution (5 mL) and then extracted with dichloromethane (2 × 5 mL). The organic phases were washed with brine solution (2 × 5 mL) and dried over anhydrous Na₂SO₄. Removal of the solvent followed by purification on silica gel column chromatography (60–120 mesh) using ethyl acetate/n-hexane gradient mixture afforded the product 6 (Table 2).

Acknowledgements

GRK, SY and MRR, CRR, thank UGC and CSIR respectively for the award of fellowships. BVS thanks CSIR, New Delhi for financial support as part of XII Five Year plan under title ORIGIN (CSC-0108).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of products. CCDC 1493462. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra21375h

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